Augusto C Montezano, Jithin Kuriakose, Katie Y Hood, Yuan Yan Sin, Livia L Camargo, Yoon Namkung, Carlos H Castro, Robson A Santos, Rheure Alves-Lopes, Gonzalo Tejeda, Patricia Passaglia, Sehrish Basheer, Emily Gallen, Jane E Findlay, Fazli R Awan, Stéphane A Laporte, Margaret R MacLean, George S Baillie, Rhian M Touyz
{"title":"Ang-(1-7)和ET-1通过Mas和ETB受体相互作用定义了一种新的血管保护机制。","authors":"Augusto C Montezano, Jithin Kuriakose, Katie Y Hood, Yuan Yan Sin, Livia L Camargo, Yoon Namkung, Carlos H Castro, Robson A Santos, Rheure Alves-Lopes, Gonzalo Tejeda, Patricia Passaglia, Sehrish Basheer, Emily Gallen, Jane E Findlay, Fazli R Awan, Stéphane A Laporte, Margaret R MacLean, George S Baillie, Rhian M Touyz","doi":"10.1161/HYPERTENSIONAHA.124.22693","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Ang-(1-7) (angiotensin (1-7)) via MasR (Mas receptor) opposes vaso-injurious actions of Ang II (angiotensin II) as shown in models of pulmonary hypertension. The underlying mechanisms remain unclear. We hypothesized cross talk between Ang-(1-7) and the protective arm of the ET-1 (endothelin-1) system involving MasR and ET<sub>B</sub>R (endothelin receptor type B).</p><p><strong>Methods: </strong>To address this, we studied multiple models: in vivo, in a mouse model of ET-1-associated vascular injury (hypoxia-induced pulmonary hypertension); ex vivo, in isolated mouse arteries; and in vitro, in human endothelial cells.</p><p><strong>Results: </strong>Pulmonary hypertension mice exhibited pulmonary vascular remodeling, endothelial dysfunction, and ET-1-induced hypercontractility. Ang-(1-7) treatment (14 days) ameliorated these effects and increased the expression of vascular ET<sub>B</sub>R. In human endothelial cells, Ang-(1-7)-induced activation of eNOS (endothelial NO synthase)/NO was attenuated by A779 (MasR antagonist) and BQ788 (ET<sub>B</sub>R antagonist). A779 inhibited ET-1-induced signaling. Coimmunoprecipitation and peptide array experiments demonstrated the interaction between MasR and ET<sub>B</sub>R. Binding sites for ET<sub>B</sub>R were mapped to MasR (amino acids 290-314). Binding sites for MasR on ET<sub>B</sub>R were identified (amino acids 176-200). Peptides that disrupt MasR:ET<sub>B</sub>R prevented Ang-(1-7) and ET-1 signaling. Using high-throughput screening, we identified compounds that enhance MasR:ET<sub>B</sub>R interaction, which we termed enhancers. Enhancers increased Ang-(1-7)-induced eNOS activity, NO production, and Ang-(1-7)-mediated vasorelaxation, and reduced contractile responses.</p><p><strong>Conclusions: </strong>We identify cross talk between Ang-(1-7) and ET-1 through MasR:ET<sub>B</sub>R interaction as a novel network that is vasoprotective. Promoting coactivity between these systems amplifies Ang-(1-7) signaling, increases ET-1/ET<sub>B</sub>R-mediated vascular actions, and attenuates the injurious effects of ET-1. Enhancing Ang-(1-7)/MasR:ET-1/ET<sub>B</sub>R signaling may have therapeutic potential in conditions associated with vascular damage.</p>","PeriodicalId":13042,"journal":{"name":"Hypertension","volume":" ","pages":"267-281"},"PeriodicalIF":6.9000,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Ang-(1-7) and ET-1 Interplay Through Mas and ET<sub>B</sub> Receptor Interaction Defines a Novel Vasoprotective Mechanism.\",\"authors\":\"Augusto C Montezano, Jithin Kuriakose, Katie Y Hood, Yuan Yan Sin, Livia L Camargo, Yoon Namkung, Carlos H Castro, Robson A Santos, Rheure Alves-Lopes, Gonzalo Tejeda, Patricia Passaglia, Sehrish Basheer, Emily Gallen, Jane E Findlay, Fazli R Awan, Stéphane A Laporte, Margaret R MacLean, George S Baillie, Rhian M Touyz\",\"doi\":\"10.1161/HYPERTENSIONAHA.124.22693\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Ang-(1-7) (angiotensin (1-7)) via MasR (Mas receptor) opposes vaso-injurious actions of Ang II (angiotensin II) as shown in models of pulmonary hypertension. The underlying mechanisms remain unclear. We hypothesized cross talk between Ang-(1-7) and the protective arm of the ET-1 (endothelin-1) system involving MasR and ET<sub>B</sub>R (endothelin receptor type B).</p><p><strong>Methods: </strong>To address this, we studied multiple models: in vivo, in a mouse model of ET-1-associated vascular injury (hypoxia-induced pulmonary hypertension); ex vivo, in isolated mouse arteries; and in vitro, in human endothelial cells.</p><p><strong>Results: </strong>Pulmonary hypertension mice exhibited pulmonary vascular remodeling, endothelial dysfunction, and ET-1-induced hypercontractility. Ang-(1-7) treatment (14 days) ameliorated these effects and increased the expression of vascular ET<sub>B</sub>R. In human endothelial cells, Ang-(1-7)-induced activation of eNOS (endothelial NO synthase)/NO was attenuated by A779 (MasR antagonist) and BQ788 (ET<sub>B</sub>R antagonist). A779 inhibited ET-1-induced signaling. Coimmunoprecipitation and peptide array experiments demonstrated the interaction between MasR and ET<sub>B</sub>R. Binding sites for ET<sub>B</sub>R were mapped to MasR (amino acids 290-314). Binding sites for MasR on ET<sub>B</sub>R were identified (amino acids 176-200). Peptides that disrupt MasR:ET<sub>B</sub>R prevented Ang-(1-7) and ET-1 signaling. Using high-throughput screening, we identified compounds that enhance MasR:ET<sub>B</sub>R interaction, which we termed enhancers. Enhancers increased Ang-(1-7)-induced eNOS activity, NO production, and Ang-(1-7)-mediated vasorelaxation, and reduced contractile responses.</p><p><strong>Conclusions: </strong>We identify cross talk between Ang-(1-7) and ET-1 through MasR:ET<sub>B</sub>R interaction as a novel network that is vasoprotective. Promoting coactivity between these systems amplifies Ang-(1-7) signaling, increases ET-1/ET<sub>B</sub>R-mediated vascular actions, and attenuates the injurious effects of ET-1. Enhancing Ang-(1-7)/MasR:ET-1/ET<sub>B</sub>R signaling may have therapeutic potential in conditions associated with vascular damage.</p>\",\"PeriodicalId\":13042,\"journal\":{\"name\":\"Hypertension\",\"volume\":\" \",\"pages\":\"267-281\"},\"PeriodicalIF\":6.9000,\"publicationDate\":\"2025-02-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Hypertension\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1161/HYPERTENSIONAHA.124.22693\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/12/5 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"PERIPHERAL VASCULAR DISEASE\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Hypertension","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1161/HYPERTENSIONAHA.124.22693","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/12/5 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"PERIPHERAL VASCULAR DISEASE","Score":null,"Total":0}
Ang-(1-7) and ET-1 Interplay Through Mas and ETB Receptor Interaction Defines a Novel Vasoprotective Mechanism.
Background: Ang-(1-7) (angiotensin (1-7)) via MasR (Mas receptor) opposes vaso-injurious actions of Ang II (angiotensin II) as shown in models of pulmonary hypertension. The underlying mechanisms remain unclear. We hypothesized cross talk between Ang-(1-7) and the protective arm of the ET-1 (endothelin-1) system involving MasR and ETBR (endothelin receptor type B).
Methods: To address this, we studied multiple models: in vivo, in a mouse model of ET-1-associated vascular injury (hypoxia-induced pulmonary hypertension); ex vivo, in isolated mouse arteries; and in vitro, in human endothelial cells.
Results: Pulmonary hypertension mice exhibited pulmonary vascular remodeling, endothelial dysfunction, and ET-1-induced hypercontractility. Ang-(1-7) treatment (14 days) ameliorated these effects and increased the expression of vascular ETBR. In human endothelial cells, Ang-(1-7)-induced activation of eNOS (endothelial NO synthase)/NO was attenuated by A779 (MasR antagonist) and BQ788 (ETBR antagonist). A779 inhibited ET-1-induced signaling. Coimmunoprecipitation and peptide array experiments demonstrated the interaction between MasR and ETBR. Binding sites for ETBR were mapped to MasR (amino acids 290-314). Binding sites for MasR on ETBR were identified (amino acids 176-200). Peptides that disrupt MasR:ETBR prevented Ang-(1-7) and ET-1 signaling. Using high-throughput screening, we identified compounds that enhance MasR:ETBR interaction, which we termed enhancers. Enhancers increased Ang-(1-7)-induced eNOS activity, NO production, and Ang-(1-7)-mediated vasorelaxation, and reduced contractile responses.
Conclusions: We identify cross talk between Ang-(1-7) and ET-1 through MasR:ETBR interaction as a novel network that is vasoprotective. Promoting coactivity between these systems amplifies Ang-(1-7) signaling, increases ET-1/ETBR-mediated vascular actions, and attenuates the injurious effects of ET-1. Enhancing Ang-(1-7)/MasR:ET-1/ETBR signaling may have therapeutic potential in conditions associated with vascular damage.
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Hypertension presents top-tier articles on high blood pressure in each monthly release. These articles delve into basic science, clinical treatment, and prevention of hypertension and associated cardiovascular, metabolic, and renal conditions. Renowned for their lasting significance, these papers contribute to advancing our understanding and management of hypertension-related issues.
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